Pharmacogenetics of ADRs: Warfarin Toxicity

描述（由申请人提供）：本研究的长期目标是确定不同种族受试者中人类CYP2C9基因遗传变异的临床后果，并了解CYP2C9酶功能活性遗传基础改变的分子机制。CYP2C9是P450的主要人类肝脏形式，代谢约15%的I期清除药物。已经证实，使用低治疗指数药物如华法林治疗具有常见CYP2C9*2和CYP2C9*3变异体的患者具有重要的临床意义。这些都是药物不良反应（adr），由于过度用药，可能导致重大的，但潜在的可避免的，患者的健康成本。尽管存在大量关于高加索人CYP2C9多态性的信息，但CYP2C9位点的全谱遗传变异以及随之而来的功能后果，尚不清楚。此外，尽管有证据表明CYP2C9基因存在群体特异性多态性，但美国其他重要的种族群体，特别是西班牙裔，在这一研究领域一直被忽视。因此，我们将；

DESCRIPTION (provided by applicant): The Iong-term aim of this research is to determine the clinical consequences of genetic variability within the human CYP2C9 gene among subjects of diverse ethnic origins, and to understand molecular mechanisms that underlie genetically-based alterations in the functional activity of the CYP2C9 enzyme. CYP2C9 is a major human liver form of P450 that metabolizes approximately 15% of all drugs that are cleared by phase I processes. It is well established that treating patients that possess the common CYP2C9*2 and CYP2C9*3 variants with low therapeutic index drugs, e.g. warfarin, has clinically important implications. These are adverse drug reactions (ADRs) due to over-medication that can result in significant, but potentially avoidable, patient health costs. Although a large body of information exists for certain CYP2C9 polymorphisms in Caucasian subjects, the full spectrum of genetic variation at the CYP2C9 locus, and attendant functional consequences, is poorly defined. Moreover, other important ethnic groups in the US, notably Hispanics, have been quite neglected in this research area, despite evidence for population-specific polymorphisms in the CYP2C9 gene. Therefore, we will; Specific Aim 1: Identify the spectrum of distal regulatory polymorphisms that exist at the CYP2C9 locus. SNP discovery will be performed in a panel of 90 DNA samples from the Polymorphism Discovery Resource. SNP validation and allele frequency determinations will then be carried out in White and Hispanic populations. Specific Aim 2: Determine the functional significance of new promoter and coding-region polymorphisms in CYP2C9. Mechanisms underlying changes in function will be probed with reporter constructs, deletion analysis, DNA/binding protein assays, recombinantly expressed proteins and stably-transfected cell lines. Specific Aim 3: Determine the impact of new CYP2C9 polymorphisms on anticoagulation-related outcomes in previously phenotyped Caucasian patients by resequencing across 60 kbp of the CYP2C9 gene from 185 pre-existing warfarin patient DNA samples. Aims 1 and 2 will test the hypothesis that; novel, functionally important polymorphisms remain to be elucidated within the CYP2C9 locus, some of which will be population-selective. Aim 3 will test the hypothesis that; promoter-region SNPs in the CYP2C9 gene are a determinant of warfarin dose. Successful completion of these studies will impact the ability of clinicians to predict the likelihood of adverse drug reactions to warfarin, and other drugs that are CYP2C9 substrates, arising in minority populations.